Dr. Simon Johnston Speaks to New ILC Research – What it Means and Its Potential Impact

In August, Breast Cancer Research published the study Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets. Lead author Simon Johnston, PhD, MBBS, provides a summary of the study while LBCA Scientific Advisory Board member Dr. Rachel Jankowitz provides a commentary on the clinical impact of the findings.

Lay Summary by Simon Johnston PhD MBBS (Lead Author), Translational Medicine, AstraZeneca

Lobular disease accounts for more than 1 in 10 cases of breast cancer.

It is often referred to as the “sneaky” subtype because it can evade detection. A lot has been learned about the unique biology of lobular breast tumors, but they are still treated the same way as other subtypes.

Looking at public data, we noticed that prognosis was worse for patients with early lobular breast cancer if tumors had a mutation in the “ERBB2” gene. This gene creates a protein called HER2. Tumors with excess HER2 respond well to HER2-targeting drugs. Lobular tumors are usually “HER2 negative.”

However, lab researchers have shown that tumor cells with certain HER2 mutations grow rapidly and also respond well to HER2-targeting drugs. We thought this may be an opportunity to treat early stage HER2-mutant lobular disease that would otherwise not qualify for HER2-targeted therapy.

To test this idea, we compared lobular with the most common subtype: ductal. We found that HER2-mutants in early lobular disease are 4 times more frequent & are more likely to respond to HER2-targeted drugs. If we do nothing, lobular patients with HER2-mutant tumors will have shorter survival.

The next step is to prove that tailored treatment for patients with HER2-mutant lobular tumors is a safe, effective and viable strategy. Gene sequencing every tumor to detect mutations would be costly. We propose a method of measuring gene activity caused by mutations in HER2, using tumor samples. This may be a more cost-effective way to detect tumors that would respond to HER2-targeted therapy.

HER2-mutants occur in 1 in 17 lobular cases, and as such represent one piece of the jigsaw. Even so, an additional 11,250 patients a year with early lobular disease could benefit from HER2-targeted therapy. We need to prioritize and co-ordinate clinical trials that tailor treatments to lobular patients.

Commentary on Clinical Impact by Rachel C. Jankowitz, MD

The authors of this study describe an important finding for a subset of patients with ILC.   They found that the relative proportion of ERBB2 mutations in primary breast tumors was higher for patients with ILC as compared to those with IDC and that the mutation was prognostic.

ERBB2/3 mutations are mutations in the HER2 gene.  A HER2 mutation is an uncommon finding in breast cancer and differs from the much more common condition of HER2 overexpression/amplification that we traditionally refer to as “HER2-positive” breast cancer.

The study investigators found HER2 mutations (either ERBB2 or ERBB3) in only 2.2% of the 1,580 cases of breast cancer studied.  However, they found that one of the mutations, ERBB2, was relatively more common in the patients with ILC (present in 5.7% of cases) compared to the patients with IDC (present in 1.4% of cases).  Moreover, they found that patients with an ERBB2 mutation in their ILC tumor had significantly worse prognosis than those whose tumors did not have the mutation.

HER2- directed therapies, including drugs like Neratinib and Trastuzumab (Herceptin), have been shown in preclinical (laboratory) studies to be effective in ILC tumors with HER2 mutations. However, patients with HER2 mutations in their tumors would not currently be offered these drugs unless they also had “HER-2 positive” breast cancer by the standard current definition.  Ongoing studies are therefore examining the efficacy of HER2-directed therapies in patients with HER2 mutations.  Early results in this arena, such as those reported by the plasmaMATCH trial in the UK, appear promising.  We eagerly await future results from these trials to help design more effective treatments for patients with HER2-mutated ILC.